These laboratories have identified participation of lysosomes in the coupled events linking capture at the plasma membrane of tropic steroid or peptide hormone with metabolic stimulation of the specific cellular target. These changes are associated with profound alterations in structure and function of the cell surface as well as with nuclear activation leading to biochemical differentiation and mitogenesis. The data support a model in which lysosomes serve as an obligatory link in nucleocytoplasmic communication prior to genic activation in such cells. Significant parallels now exist in more extensive lysosome labilization by a variety of noxious agents, comprising bacterial toxins, carcinogens (including those of viral origin), radiation, and even excess concentrations of heavy metals such as prevail in urban environments. The present application proposes to extend analysis of the role of lysosomes and their extruded components, including highly stringent proteinases, nucleases, and glycosidases, as well as acidic glycoproteins, in mediating the growth-promoting and growth-inhibitory effects of selected hormones and of certain agonists known to elicit neoplastic transformation. The studies will comprise analysis of biochemical, enzymatic, and morphologic profiles of populations of epithelial cells from selected target and control organs, with respect to graded modification of lysosomal membrane stability by these agonists. Particular emphasis will be placed on analysis of nuclear components for constituents translocated from lysosomes, using PAG electrophoresis coupled with immunochemical procedures. Complementary investigations will be carried out on potential blockade of metabolic and mitogenic correlates by naturally-occurring and synthetic lysosome membrane-stabilizing substances, metabolic antagonists to specific lysosomal hydrolases, and by antibodies directed against lysosomal constituents. These efforts may contribute a useful approach to certain unresolved problems in regulation of cell growth and differentiation in response to specific chemical signals.